Major depressive disorder (MDD) is a common illness that often has chronic or recurring course. Prevention is believed to be the key to reducing the burden of this disorder. However, an effective prevention program requires thorough knowledge of predisposing factors and mechanisms by which they convey risk. Personality characteristics are powerful predictors of MDD onset, but it is not yet clear which traits are the best markers of vulnerability. Also, the mechanisms underlying these links are not well understood. This project aims to identify main personality risk factors for depression onset and elucidate relevant etiologic processes, including interactions with life stress as well as neural and endocrinal mechanisms. Another objective is to learn how much concomitant depression distorts scores on personality measures, thus informing basic personality research and clinical assessment. We propose to recruit 575 14- and 15-year-old females (demographic stratum at highest risk for incident depression) who have never experienced a major depressive episode. Participants will be assessed in person three times: at baseline, month 18, and month 36. They will complete a thorough diagnostic interview, a battery of personality scales, as well as measures of negative life events, daily functioning, cortisol levels, and brain activity. They also will participate in brief phone interviews between assessments to minimize biases in recall of depressive episodes and stressful life events. Family psychiatric history and informant-ratings of personality will be obtained from a parent. We will use Structural Equation Modeling (SEM) to estimate trait scores with high precision, and growth modeling to remove distortions in these ratings induced by concomitant depression. We expect these analytic strategies to substantially enhance power of our analyses and will develop formulas for correcting personality scores in future studies. Next, we will examine the dynamic interplay between personality and environment in development of vulnerability to MDD. We also will test two promising biomarkers of pathological developmental trajectories. Furthermore, we will develop a personality screen to identify adolescents at risk well before they experienced depression. This multidisciplinary project will form the basis for a program of research that ultimately seeks to design and target new preventive interventions for adolescent depression.